NOVEL NONSTEROIDAL INHIBITOR OF CYTOCHROME P450(17-ALPHA)(17-ALPHA-HYDROXYLASE C17-20 LYASE), YM116, DECREASED PROSTATIC WEIGHTS BY REDUCING SERUM CONCENTRATIONS OF TESTOSTERONE AND ADRENAL ANDROGENS IN RATS/

BACKGROUND. The purpose of this study was to determine the effects of a nonsteroidal C17-20 lyase inhibitor, 2-(1H-imidazol-4-ylmethyl)-9H-c arbazole (YM116), on serum concentrations of androgens and ventral pro static weight in rats. METHODS. Serum concentrations of testosterone a nd of dehydroepiandrosterone sulfate and prostatic weights were measur ed in rats treated with YM116. RESULTS. YM116 inhibited testicular C17 -20 lyase competitively (Ki,0.38 nM), and decreased the serum testoste rone concentration in gonadotropin-releasing hormone-treated rats (ED5 0, 0.7 mg/kg), indicating that YM116 was about 21-24 times more potent than other C17-20 lyase inhibitors such as ketoconazole and liarozole , and was twice as potent as CB7630. YM116 also reduced dehydroepiandr osterone sulfate levels in ACTH-treated castrated rats (ED50 11 mg/kg) . YM116 (40 mg/kg, p.o., for 2 weeks) was almost comparable to bilater al orchiectomy with respect to the time course and magnitude of the re duction in prostatic weight. Each of these two treatments decreased th e prostatic weight 3 days following the treatment. Contrarily, leuprol ide transiently increased the prostatic weight and then decreased it. YM116 (100 mg/kg) had no effect on the serum cortisol level in guinea pigs, and slightly decreased the serum aldosterone level in rats. CONC LUSIONS. YM116 is a selective C17-20 lyase inhibitor which decreases r at prostatic weight by reducing androgen production in the testes and adrenal glands. Prostate 37:10-18, 1998. (C) 1998 Wiley-Liss, Inc.